Ocular treatment device

ABSTRACT

A unit container for a treatment fluid comprises a sealed enclosure of which one wall section thereof is formed with at least one opening. The enclosure is pressuriseable to discharge its contents thorough the opening or openings, which is or are of sufficient diameter to enable the generation of a jet and/or discrete droplets of treatment fluid discharged therefrom. The one wall section is typically a flat section of the enclosure wall, and the enclosure is typically a blister pack, with the wall section at a planar base of the blister. However the one wall section may be dome-shaped and formed with at least one opening in the top region of the dome. Containers of the invention may be provided in packages, for example in strip form or in planar arrays. Dispensing devices are described for discharging their content in treatment.

[0001] This invention relates to ocular treatment devices, andparticularly to a device of the kind which is operable to deliver to theeye treatment fluids in the form of a jet and/or small droplets.

[0002] Ophthalmic treatment fluids are commonly administered to the eyeby means of eye drops or ointments. The use of eye drops has a number ofdisadvantages, primarily as a consequence of the difficulty with whichdrops are accepted by the patient. The drops are relatively large, andthe instinctive blink that is provoked by the arrival of a drop on theeye severely limits the amount of or proportion of fluid that actuallycontacts the target area on the eye. Typically less than 10% of a 50μldrop can be effective, the remainder being lost by drainage, eitherexternally or through nasolacrimal drainage. Such use of expensivetreatment fluids is wasteful, as well as leading to substantialuncertainty regarding the effectiveness of a treatment. Similar commentsapply to the use of ointments, although levels of wastage can be reducedby careful delivery. The greater viscosity of ointments reduces theirtendency to drain or be washed away.

[0003] In our International Patent Application No. PCT/GB95/01482 thereare proposed various techniques for delivering treatment fluid to theeye. These employ systems in which treatment fluid is drawn from areservoir and discharged in a controlled manner to the eye. While thesetechniques are useful, there are difficulties arising from the repeateduse of the multidose nozzle. Specifically, it is difficult to maintainthe sterility of the treatment fluid in a system in which doses of fluidare successively drawn from a reservoir, and passed through a re-usablenozzle without the use of preservatives. The use of preservatives hascaused some concern as discussed on pages 8-11 of “Ophthalmic DrugDelivery Systems” (Drugs in the Pharmaceutical Sciences, Volume 58),published in 1993 by Marcel Dekker.

[0004] Reference is also directed to U.S. Pat. No. 3,934,585 whichdiscloses a variety of mechanisms for delivering unit doses of treatmentfluid to the human eye. The doses are held in dispensing tubes which arefitted in the mechanisms when treatment is required. The mechanisms areoperative to apply compressed air to one end of a tube resulting in thedischarge of treatment fluid from the other end.

[0005] It is an aim of the present invention to minimize or eliminatethe need to use preservatives in ophthalmic treatment fluids withoutrisking contamination. Thus, in a primary aspect, the present inventionprovides a unit container for a treatment fluid comprising a sealedenclosure of which one wall section thereof is formed with at least oneopening, the enclosure being pressuriseable to discharge its contentsthrough said at least one opening, which opening is of sufficientdiameter to enable the generation of a jet and/or discrete droplets oftreatment fluid discharged therefrom.

[0006] The wall section of a container according to the invention formedwith the opening or openings is typically a flat section of theenclosure wall, and the enclosure is typically a blister pack, with thewall section at a planar base of the blister. However, we have foundthat some particular benefits arise from the adoption of a non-planarwall section in which the opening or openings are formed. Moreparticularly, we have found that the adoption of a dome shape in therespective wall section can result in a more reliable performance of thecontainers in use, and facilitate certain other beneficial developmentsof the containers. Thus, in preferred embodiments of the invention, aunit container for a treatment fluid comprising an enclosure of whichone wall section is dome shaped and formed with at least one opening inthe top region of the dome shape, the enclosure being adapted to confinea sealed volume of treatment fluid, and pressurisable to discharge thecontents of the sealed volume through said at least one opening. One ormore other wall sections may also define a dome shape complementary tothat with the opening, which is capable of inversion into the one wallsection in the discharge of the container contents.

[0007] The enclosure of a unit container of the invention can bepressurised by the application of an external force on the side of theenclosure opposite the wall section formed with the opening or openings.Where the respective wall section is substantially flat, this method ofpressurising the enclosure contents can create high stresses in the wallsection, and particularly around the opening or openings. In somesituations, this can result in the wall section itself tearing aroundthe opening or openings with the consequence that the discharge of theenclosure contents becomes less predictable. By locating the opening oropenings at the top of a dome shape, these stresses are reduced.

[0008] Either a single opening or an array of openings may be found inthe respective wall section of the container. Various arrays arepossible, and a particular choice will be influenced by a number offactors. A larger number of openings will dispense treatment fluid overa larger target area. Smaller openings produce narrower jets and/orsmaller drops which will be subject to greater deceleration in theirpassage to the target area. This may allow the use of higher pressures.A single opening can direct a jet or stream of drops accurately to aspecific target area, and minimize the time taken to deliver thetreatment fluid to beat the blink response. The preferred minimumopening diameter is at least 10 μm to avoid creating a spray of dropletswith insufficient linear momentum to reach their target. The use of asingle opening of 100 μm diameter is particularly preferred. Theintention is to create droplets no smaller than say 20 μm to avoid thecreation of an inhalable spray.

[0009] Another benefit arising from the adoption of a dome shaped wallsection in which the opening or openings are defined is that dischargeof substantially the entire contents of the enclosure is facilitated. Ifthe device used to pressurise the enclosure is a piston or hammer, itsoperative end can be shaped to complement that of the dome such that inoperation the other wall sections of the enclosure, which can similarlybe shaped to complement that of the dome, are inverted against the domeshaped wall section thus substantially evacuating the entire enclosure.

[0010] The wall section of the enclosure in a container of the inventionmay be provided with a removable cover overlaying the opening oropenings, which cover is only removed just prior to the contents of theenclosure being discharged. In this way, the contents are protected fromthe environment until required. In an alternative arrangement the oreach opening in the wall section of the enclosure is closed by amembrane adapted to rupture upon pressurisation of the enclosure. Thesemeans demonstrate how treatment fluids can be kept sterile in containersof the invention. As a consequence, the need for the use ofpreservatives in the contents is minimised or eliminated.

[0011] The use of a dome wall section in preferred containers of thepresent invention facilitates the creation of a separate sealed volumewithin the enclosure. In these circumstances, the removable coveroverlaying the opening or openings can be dispensed with, or at leastthe requirements for its sealing qualities can be reduced. According tothis aspect of the invention, which can of course also be applied to acontainer without a dome shaped wall section with the opening oropenings, a dividing wall is included within the enclosure, whichdividing wall separates the wall section with the opening or openingsfrom a region within the enclosure which defines the sealed volume. Thedividing wall is adapted to rupture prior to discharge of the contentsfrom the enclosure. Conveniently, the dividing wall can be adapted torupture upon pressurisation of the enclosure as part of the step ofdischarging the contents of the sealed volume through the opening oropenings in the wall section. However, the dividing wall may be adaptedto rupture upon the application of an external force prior topressurisation of the enclosure. Particularly, when the container isfitted, either as an individual unit or as part of a strip for example,in a dispensing device, a mechanism can be included to apply tensileforce across the container to break the dividing wall just prior to theenclosure being pressurised.

[0012] Where a container according to the invention defines a sealedvolume with a dividing wall, it will be understood that this sealedvolume can be formed as a individual component of the container prior toattachment of the wall section formed with the opening or openings. Thisfeature also offers a number of particular benefits, primarily in themanufacture of packages containing a plurality of complete containers.Manufacturing these components individually means they can be separatelychecked for defects prior to incorporation in a package. It alsofacilitates the creation of packages having containers with differentdosages; either different treatment fluids or different quantities ofthe same fluid, and also enables a plurality of individual components tobe disposed under a common dome shaped wall section, whereby differenttreatment fluids can be kept isolated, but mixed just prior to dischargefrom the opening or openings.

[0013] Containers of the invention are designed to provide for thesuccessive or simultaneous delivery of a jet or small droplets,sometimes in the form of a stream or spray, which may be diffuse orcollinear. A typical range for the size of opening in the wall sectionof the enclosure to achieve is up to 1000 μm, preferably 20 to 200 μm. Aparticularly preferred size range is 100 to 150 μm. A single opening oran array of openings can be used, conveniently punched, drilled,electroformed or laser-drilled in a plastics sheet or foil defining thewall section. A metal, typically a nickel foil is preferred forelectroforming.

[0014] The form of delivery that is appropriate for a particularophthalmic treatment; ie, single or multiple openings, and thearrangement thereof, will be dictated by the need to achieve asufficient delivery rate to beat the “blink response”, with minimaladverse reaction or unpleasant sensation to the eye. Thus, if a higherquantity of fluid must be delivered, in order to ensure delivery priorto the patient blinking, and at a tolerable impact speed, multipleopenings will be used instead of a single opening to achieve asufficient overall delivery rate.

[0015] Unit containers according to the invention can be charged suchthat each enclosure confines a prescribed unit dose for dischargetherefrom, typically no more than 10 μl . However, larger volumes suchas 20, 50 or 100 μl could be required, for example for irrigationpurposes. A plurality of containers may be provided in the form of apackage, conveniently on a common substrate, and preferably in the formof a strip with the containers arranged sequentially therealong.

[0016] The discharge of the contents of enclosures in containersaccording to the invention can most simply be accomplished by provokingthe collapse of the enclosure wall, against the section having theopening or openings, preferably by a mechanical system. The wall mayinclude a reinforced region to orient its collapse. For example, theenclosure might be crushed from the side opposite the wall section by apiston, hammer or cantilever mechanism, the action of which may bedampened to control the speed of the mechanism, with sufficient impactto discharge and project the contents a predetermined minimum distance.In an alternative, the enclosure might be formed as a cylindricalchamber, with an opposite wall portion formed as a piston for movementtowards the wall section to force the enclosure contents through theopening or openings.

[0017] The invention is also directed at devices for discharging atreatment fluid from the sealed enclosures of containers of the typedescribed above. Such a device comprises a package of the containers; amechanism for feeding the containers seriatim to a dosing station; andmeans for acting on the enclosure of a container at the dosing stationto discharge the contents thereof. The invention also provides a manualfeed device in which provision is made for individual containers orpackages thereof to be fed manually to the dosing station as required.When the wall section of the container enclosure has a cover, the devicecan include means for its removal prior to discharge of the enclosurecontents. This means may be synchronised with the feeding mechanism.

[0018] The discharge of the contents of the enclosure at the dosingstation in the above device is preferably accomplished by pressure suchthat it is forced through the opening or openings in the respective wallsection of the enclosure. However, in an alternative, an electrostatictechnique can be used, broadly of the kind described in publishedEuropean Patent Specification No. 0 224 352. For this alternative, theinvention provides a modified unit container in which the enclosure isnot specifically pressurisable, but has a wall which includes aconductive section for connection to a source of electrical potential,whereby application of such potential generates an electrical charge inthe container contents, and its discharge through said at least oneopening.

[0019] In discharging devices of the invention in which the discharge ofthe container contents is accomplished by pressurising its enclosure,the preferred means is a physical mechanism such as a crushing unit foracting directly on the outside of the enclosure from the side oppositethe wall section formed with the opening or openings. This can take theform of a piston-cylinder mechanism, and such a mechanism can also beused to move an opposite wall portion in a cylindrical enclosure of thekind described above.

[0020] Another technique that can be used to pressurise the enclosure incontainers of the invention uses piezoelectric elements. Such elementsenable the degree of pressurisation achieved to be accuratelycontrolled, and can be disposed for example, against a face of theenclosure opposite the wall section,or in the form of a ring around thebody of the enclosure. In either arrangement such an element can beoperated selectively or repeatedly to discharge discrete droplets or arapid sequence. The element may take the form of an ultrasonictransducer, one which is particularly suited to the generation of aspray through an array of openings in the wall section of the enclosure.

[0021] Other features can also be employed in devices according to theinvention to indicate the successful delivery of a treatment fluid toits target. A light can be provided to maintain the eye open, and thiscould typically be white. Alternatively, a coloured system may beemployed in which a different colour indicates the stage of treatment.For example, the device can be offered up to the eye showing a redlight, which will switch to green only after the predetermined dose hasbeen dispatched.

[0022] Devices according to the invention can also include a number ofsafety features which are already well established in dosing devices ofvarious kinds. The number of containers in a device will of course befinite, and a dose recorder may be included to provide an indication ofthe number of doses remaining or delivered. A delay mechanism can alsobe included to prevent the inadvertent delivery of a multiple dose. Incombination with the delivery signal features referred to above, thiscan be of significant benefit.

[0023] It will be recognised that devices according to the invention canbe for personal or hand held use, or for use on a more regular basis ininstitutions. For whatever use, means can be provided for ensuring aproper spacing between the device and the eye to be targeted, and thiscan be made adjustable, particularly in the devices adapted forinstitutional use. In this respect, it will be noted that the mechanismscontemplated in the present invention will be well capable ofdischarging a jet and/or droplets substantially horizontally orvertically upwards over a minimum distance, thereby not requiring a userto arrange for the device to be operated from directly above an eye.

[0024] In addition to the containers and devices discussed above, thepresent invention also provides methods of generating jets and/ordroplets and of treatment, using such containers and devices. Themethods of treatment additionally require the targeting of generatedjets and/or droplets at a respective treatment site.

[0025] The invention will now be described by way of example and withreference to the accompanying schematic drawings wherein:

[0026]FIG. 1 is a perspective view of a device in which the enclosure ofa unit is crushed to discharge its contents;

[0027]FIG. 2 is a detailed view of the crushing unit in the device ofFIG. 1;

[0028]FIG. 3 is a perspective view of a device in which a pistonmechanism is used to discharge the enclosure contents;

[0029]FIG. 4 is a detailed view of the piston unit of FIG. 3;

[0030]FIG. 5 is a perspective view of a device in which a piezoelectricdevice is used to discharge the enclosure contents;

[0031]FIG. 6 is a detailed view of the piezoelectric unit of FIG. 5;

[0032]FIG. 7 is a perspective view of a device similar to that of FIGS.5 and 6 but for use with individual containers;

[0033]FIG. 8 is a detailed view showing a container being presented tothe piezoelectric unit;

[0034]FIG. 9 is a perspective view of a device which uses anelectrostatic charging system to discharge the enclosure contents;

[0035]FIG. 10 is a detailed view of the dosing station of the unit ofFIG. 9;

[0036]FIG. 11 is a cross-section through a preferred container accordingto the invention;

[0037]FIGS. 12A, 12B and 12C illustrate cross-sections at differentstages in the manufacture of another preferred container according tothe invention;

[0038]FIG. 13 illustrates yet another preferred container according tothe invention;

[0039]FIG. 14 shows in plan view a length of strip or bandolier formedwith unit containers in the form of sachets embodying the invention;

[0040]FIG. 15 illustrates a simple compression device for dischargingthe contents of a sachet of the type illustrated in FIG. 14; and

[0041]FIG. 16 shows the device of FIG. 15, having been activated todischarge the sachets contents;

[0042]FIG. 17 shows in cross-section yet another unit dose containerembodying the invention;

[0043]FIG. 18 shows a device for discharging the contents from acontainer as shown in FIG. 17; and

[0044]FIG. 19 is a graph showing the miotic response of rabbitssubjected to treatment using the device of FIG. 18.

[0045] The device shown in FIG. 1 comprises a housing 2 with an opencowling 4 at one end with the dosing station 6 of the device disposed atthe base thereof. The device shown is for ophthalmic treatment, and thecowling serves to ensure that the dosing station is located correctlyand spaced a proper distance from the eye for a treatment to beeffective. . Containers according to the invention are mounted on a tape8 which extends from a supply cord 10, around in front of the dosagestation 6 and on to a take-up reel 12. A capstan 14 is provided to windthe tape on to locate a fresh container at the dosage station fordischarge of its contents. A button 16 is shown for initiating theactivation of the dosage station when it is properly charged. Theenclosure of each container on the tape 8 takes the form of a blisterpack 18 depending from a continuous backing 20, as is better shown inFIG. 2. The open face of the blister pack 18 is closed by a continuousmetal foil 22, and over each blister the foil has ten 40 micron openingselectroformed therein. Overlaying the foil is a cover layer 24, which isprogressively removed from the foil as a blister pack reaches the dosagestation 6. It is removed by a spring loaded take-up reel 26, which drawsthe cover layer around a guide bar 28 on the upstream side of the dosagestation. A similar guide bar 28 is located on the downstream side of thedosage station, and the tape 8 is held thereagainst by means, of springloaded beams 30. These beams 30 are spaced by a distance substantiallyequal to the dimension of the blister 18 along the length of the tape 8such that they also serve to locate the blister centrally at the dosagestation 6.

[0046] The dosage station shown in FIG. 2 includes a piston 32 in ablock 34, which is itself mounted in a housing 36 and located therein bymeans of a latch 38. To provoke the discharge of the contents of theblister pack 18 through the openings in the foil 22, the button 16 isdepressed to release a spring (not shown) which charges the piston 32against the blister 18, and crushes it against the foil 22. The capstan14 is then turned to bring the next charged blister into alignment withthe piston, and the capstan 14 will also be coupled to the piston 32 toretract it to its starting position prior to the fresh charged blisterreaching its discharge position.

[0047] In the device shown in FIG. 3 the container enclosures 40 aremounted on a bandolier 42 which, as with the embodiment of FIG. 1,extends from a supply reel 44 past a dosage station 46 and on to atake-up reel 48 coupled to a capstan 50 for winding on. The housing 52has a cowling 54, but it will be noted that the orientation of thehousing relative to the cowling is different.

[0048] At the dosage station which is better shown in FIG. 4 eachenclosure 40 is successively aligned with the piston 54 of the cylindermechanism 56. Each enclosure 40 is cylindrical, and has at its forwardend a nozzle 58 with one or a plurality of openings therein. This end isclosed by a foil seal 60. The other end of the enclosure 40 is closed bya silicone piston 62, and when the dosage station is activated thepiston 54 engages the piston 62 and thus compresses enclosure contents.This pressure forces the contents through the opening or openings 58,simultaneously discarding the foil seal 60, and the contents are thendischarged in the form of a spray as indicated at 64.

[0049] The device shown in FIGS. 5 and 6 is in some ways similar to thatof FIGS. 1 and 2, but in this embodiment discharge is effected by meansof a piezoelectric element. A tape 66 comprising discrete containers iswound on by means of a capstan 68 to locate a container at the dosagestation 70. At the dosage station the enclosure 72 of the container isaligned with a piezoelectric ring transducer 74 while a cover layer 76is removed in substantially the same manner as it is in the embodimentof FIG. 1. Removal of the cover again exposes a metal foil 78 overlayingthe blister 72 and formed with ten 40 micron electroformed openings.

[0050] As with the dosage station illustrated in FIG. 2, in thisembodiment it comprises a piston 80 mounted in a cylinder 82 itselflocated in a housing 84 by means of a latch 86. Depression of the button88 activates a spring to move the piston towards the blister 72, butonly to locate the piezoelectric ring transducer 74 around the bodythereof. Means (not shown) then activate the transducer 74 to contractit around the blister 72 and thus discharge the contents thereof throughthe openings in the metal foil. Again, and as described above withreference to FIGS. 1 and 2, winding the tape on with the capstan 68 alsoretracts the piston 80. However, in this embodiment the capstan 68 alsoactuates a knife to detach the used blister from the tape 66, which isthen ejected through an opening 88 in the device housing.

[0051]FIGS. 7 and 8 illustrate what can be regarded as a simplifiedversion of the embodiment of FIGS. 5 and 6. In this embodiment, thecontainers are provided separately, and the housing 90 of the device isprovided with a storage compartment 92 for the container supply. Whenthe device is to be used, a container 94 must be removed from thestorage,compartment 92 and manually fitted to the ring transducer 96fixed at the base of the cowling 98 of the housing. A battery 100 andthe requisite electronics 102 are disposed in a chamber 104 locatedbetween the storage compartment 92 and the transducer 96. To use thethus charged device, a cover 106 is removed from the visible face of thecontainer 94 to expose a wall section 108 of the enclosure formed with a50 micron nozzle. When the electronics 102 are activated by a button(not shown) the ring transducer 96 contracts around the container 94 todischarge its contents through the nozzle.

[0052] As can be seen, the enclosure of the container 94 is reinforcedaround its inner perimeter by a section 110. This inhibits rupture ofthe enclosure upon contraction of the ring transducer, and its internalshape also serves to increase the discharge velocity of fluid from theenclosure through the nozzle.

[0053]FIGS. 9 and 10 illustrate an alternative embodiment of theinvention in which the contents of the enclosure are discharged by meansof an electrostatic charging system. A covered strip 112 of containers114 is provided in the housing 116, with a capstan 118 for advancing thestrip 112 to locate a container 114 at the dosing station 120, broadlyin the manner described with reference to FIGS. 1 and 2. In thisembodiment however, the enclosures 122 of the containers 114 are formedof an electrically conductive material. A contact 124 is located at thedosing station 120 to engage the enclosure wall, and a switch (notshown), activated by the dispense button 126 is provided to apply anelectrical potential from a generator 128 to the enclosure wall tocharge the contents and force their discharge through the opening 130.Power for the generator 128 is provided by a battery 132, also locatedin the housing 116. Because the enclosure wall in each container isconductive, they must be isolated from each other in the strip 112.Thus, as shown in FIG. 10, the strip has an insulating section 134between the containers 114.

[0054] Provision can be made for devices of the invention to deliverdifferent fluids to a target site in a composite treatment. Thus,containers enclosing different fluids can be included for feeding to thedosing station, and where the containers are mounted on a strip orbandolier, then a chosen sequence can be predetermined. For example, ananaesthetic or diagnostic aid such as fluorescein might be enclosed inalternate containers mounted on a strip.

[0055] FIGS. 11 to 13 illustrate preferred containers for use in thedevices described above, which are of “double-dome” construction. Thecontainer shown in FIG. 11 defines an enclosure 202 in which is held aquantity of treatment fluid 204. The lower part of the container asshown is created as a blister in a foil laminate base sheet 206 which isoverlaid with a foil laminate upper sheet 208 which is formed into adome where it defines the upper part of the enclosure 202. The base andupper sheets 206, 208 are bonded where they contact one another to sealthe enclosure at the junction therebetween.

[0056] In the top section of the upper sheet 208 is formed an opening210, which is closed by a cover sheet 212 making sealing engagement withthe external surface of the upper sheet 208 around the opening 210. Thecover sheet 212 is typically a plastics sheet or a metal foil.

[0057] In use, the container shown in FIG. 11 is fitted in a devicewhich properly locates the enclosure 202 relative to means such as apiston or air pressure source, for forcing the base sheet 206 where itforms the lower part of the enclosure 202, towards the opening 210 andagainst the upper sheet 208. The cover sheet 212 is removed, and thesystem actuated. As a consequence, the treatment fluid 204 in theenclosure 202 is discharged through the opening 210 towards its chosentarget.

[0058] FIGS. 12 illustrate a container in which individual components ofthe container can be prepared separately with treatment fluid therein,and thereafter attached to an upper sheet which completes the respectivecontainers. Such a component is shown in FIG. 12A, which consists of abase sheet 206 formed into a blister to hold a quantity fluid 204. Theblister is closed by an intermediate layer 214 sealed around theperiphery of the blister to the base sheet, but including a weakenedsection 216 which actually overlays the blister. Nevertheless, thecomponent illustrated is sealed, and the treatment fluid 204 in theblister is properly protected from contact with the external atmosphere.It also allows autoclave sterilisation of the sealed volume.

[0059]FIG. 12B shows a section of upper sheet 208 formed with an opening210 for disposal over the blister of the component shown in FIG. 12. Theassembled combination is shown in FIG. 12C.

[0060] Each component shown in FIG. 12A is manufactured as a discreteelement, and may be subject to quality control examination to ensurethat as a treatment fluid dosage component, it is sound in everyparticular. To complete a container from which the treatment fluid 204may be discharged in accordance with the invention, an upper sheet 208is laid and sealed thereover with its domed section including theopening 210 disposed directly opposite the blister in which thetreatment fluid 204 is held. If a strip of containers is to be formed,then a continuous length of upper sheet 208 formed with a series ofdomed sections can be used to simultaneously complete and interconnect apackage of containers according to the invention. Such a package isillustrated in FIG. 12C.

[0061] The use of a container of the type illustrated as part of thepackage of FIG. 12C is generally similar to that of FIG. 11, with twoessential differences. Firstly, a cover sheet 212 is not essentialbecause the treatment fluid 204 is already sealed within the volumedefined within the container by the layer 214. Nevertheless, some formof cover sheet might still be used, although it will be understood thatthe bond between the cover sheet 212 and the upper sheet 208 around theholes 210 does not have to be effective to seal the enclosure to thesame extent as it does in the embodiment of FIG. 11. Secondly, when theenclosure is pressurised, and particularly when the sealed volumecontaining the treatment fluid 204 is compressed, the first effect isthe rupturing of the weakened section 216 of the layer 214, and theweakened section 216 may be designed to rupture along a defined axis.Thereafter, the discharge is essentially similar to that of theembodiment of FIG. 11. The weakened section 216 may also absorb some ofthe crushing force during the collapse of the blister, resulting inlower pressures and a reduced tendency of the blister or dome to burstor tear.

[0062] If because of the pressurising system used or for any otherreason, there is a need to rupture the weakened section 216 prior toactual pressurisation of the enclosure, this can be accomplished. Thedischarge device used can be adapted such that the laminate of base andupper sheets 206, 208, and layer 214 is gripped on either side of theblister, and stretched across the blister to rupture the weakenedsection 216 before a piston for example, engages the base sheet 206 tocollapse the enclosure. The direction of such stretching is indicated bythe arrows shown adjacent the container shown on the left-hand side ofFIG. 12C.

[0063]FIG. 13 shows a container in which two treatment fluids can beconfined separately in the same enclosure, within respective sealedvolumes closed by weakened sections of an intermediate layer 214. Themanufacture, assembly and use of the container is essentially similar tothose described with reference to FIGS. 12, but FIG. 13 also illustratesa piston or hammer 218 for effecting discharge of the treatment fluidsthrough the opening 210.

[0064] It will be appreciated that the shapes of the blister in thesheet 206 and the dome in the sheet 208 can be made complementary suchthat when a piston such as 218 is applied to the blister, or blisters asshown in FIG. 13, the entire section of sheet defining the blister orblisters eventually engages the section of sheet defining the dome tosubstantially completely evacuate the enclosure of the treatment fluidor fluids previously contained therein. This of course is particularlyimportant in treatments where dosages must be accurately defined.

[0065] The separate manufacture of individual components of containersin accordance with the invention facilitates not only quality control,but also sterilisation and other preparatory procedures. In theembodiments described above, a foil laminate upper sheet 208 can be usedin which only a single opening 210 is formed. However, particularlywhere a plurality of openings are required, the preferred material forthe upper sheet 208 is a metal foil in which openings are made byphotoresist electroforming. The bonding of metal foils directly tolaminated base sheets can have a deleterious effect upon treatment fluidotherwise exposed in the blister. These effects are much reduced wherethe treatment fluid is already confined in its own sealed volume underthe intermediate layer 214, and where the upper sheet is bonded to theintermediate layer 214.

[0066] In some instances it may be desirable to have a smooth dischargeof treatment fluid through the opening or openings in the dome shapedwall section, or indeed the opening or openings through which fluid isdischarged from any of the containers described herein. To this endpreferred opening or openings should taper towards the discharge end,with the inlet diameter typically of the order of three times that ofthe outlet. The preferred axial length of the opening or openings is 1to 5 times the outlet diameter, and at the outlet the opening may bemade substantially cylindrical.

[0067] The terms “dome” and “dome shaped” have been used in the abovedescription of FIGS. 11 to 13 in a very broad sense. They are notintended to define a particular or necessarily symmetric form of closurein containers of the invention. Others could be used to equivalenteffect. What is however important, is the disposition of the opening oropenings in the top region thereof whereby discharging fluid is directedtowards the opening or openings as the enclosure is pressurised.

[0068] In the system illustrated in FIGS. 14, 15 and 16, individualsachets 222 of treatment fluid are mounted on a strip 224. Each sachet222 is pear-shaped, and held in the backing or support sheet 226 for useas needed. Each sachet has a weakened wall section 228 located adjacenta cut out in the support sheet 226.

[0069] In use, the strip 224 is moved in a device (not shown) to locatea sachet 224 at a discharge station. At the discharge station twoopposing pistons or hammers 230 are caused to accelerate towards eachother. This compresses the sachet 224 as shown in FIG. 16 to force thecontents of the sachet therefrom in the direction shown. The pistons orhammers are then withdrawn, releasing the emptied sachet which is thendiscarded.

[0070] The weakened wall section 228 can be very small, in order toaccurately focus the discharge on the chosen target. Further, it canhave a line of weakness across a diameter, or alternatively an array ofweak points which rupture in a pre-ordained manner.

[0071] The container shown in FIG. 17 comprises juxtaposed sheets 232and 234 of for example, 30 μm aluminium foil laminate and 40 μm copperfoil respectively, shaped and held around a continuous path in a hotmelt adhesive layer 236 to form a sealed bubble in which is confined an8 μ1 unit dose 238 of a treatment fluid. Each sheet 232, 234 formssubstantially half the bubble wall, and at the apex of the dome formedby the copper foil layer 234 a single 100 μm opening is made, typicallyby punching, drilling, electroforming or laser-drilling. The layer 236forms flanges on either side of the bubble, and a strip of containersmay be made, interconnected by a continuous length of the layer 236.

[0072] The device shown in FIG. 18 has a dosing station 240 with twopairs of clamping plates 242 which define a path for a strip ofcontainers of the kind illustrated in FIG. 17 with continuous flangesformed by the layer 236 disposed between respective plate pairs. Whenthe device is ready to operate, the plates 242 clamp together to holdthe flange and therefore the bubble in the appropriate position in thedosing station. The plates may be clamped by twisting the elements 244,or by an automatic mechanism activated by triggering the device.

[0073] Location of a container at the dosing station aligns it with anelongate piston 246 mounted for axial linear movement within a mainhousing 248. The piston 242 is principally supported in a back panel 250mounted on the housing 248, and is guided at its forward end by a guidescrew 252, to which the piston is attached. Compressed between the panel250 and the guide screw 252 is a spring 258, and it is held compressedby a catch 254 which engages the forward face of the guide screw 252.Operating the trigger mechanism 254 releases the guide screw 252 andpiston 246 which is then driven by the spring 258 to engage the nearerside of the “bubble” and force the contents out of the container throughthe 100 μm opening. To “re-cock” the device for further use, the piston246 is merely withdrawn to the left as shown against the force of thespring 258 until the guide screw 252 latches behind the catch 254. Theguide screw 252 is balanced by a counterweight 256 at the other end ofthe piston 246, which can also be used to pull the piston back againstthe force of the spring.

[0074] The device of FIG. 18 was used in a study of the ocular responseof rabbits to treatment according to the invention. The rabbits selectedfor the study were allowed to acclimatise for 4-5 days prior totreatment. They were subjected to manual restraining for 2 days prior tothe study to condition them to the procedures involved in dosing. Adevice of the kind illustrated in FIG. 18 was then used to administer asingle spray of isotonic 2% Pilocarpine hydrochloride (Pilocarpine HCl)solution to the corneal surface of the left eye of each of 5 rabbits,the right eyes remaining undosed. The following settings were used:

[0075] 100 μm nozzle diameter

[0076] 2.5 cm distance between nozzle tip and animal eye

[0077] Sprays targeted towards the center of the cornea of the animaleye

[0078] The miotic response (reduction in pupil diameter) at variousintervals following the application of the pilocarpine HCl solution wasmonitored under constant illumination using video photography. The pupildiameter of the left eye was expressed in proportion to the diameter ofa fixed reference aperture situated at an equal distance from the videocamera. The actual diameter was then calculated from the known diameterof the reference aperture.

[0079] Table 1 shows the pupil diameter of the left eye at differentintervals following application of the test dose, as is representedgraphically in FIG. 19. TABLE 1 Pupil Diameter (mm) FollowingApplication of 2% Pilocarpine HCl Using a Laboratory Model BlisterCrushing Device (Mean of 5 Rabbits) Measurement Timepoint Dose +15 +30+45 +1 +1.5 +2 +2.5 +3 +3.5 +4 (0 min) min min min hr hr hr hr hr hr hrMean 7.8 6.7 6.8 6.9 6.8 6.9 7.3 7.8 7.9 8.0 7.8

[0080] Devices according to the invention can typically generatedroplets with diameters of the order of 200 μm, enabling the delivery ofmultiple droplets in metered doses of very low volume, 5 μl beingtypical. However, smaller droplets can be desirable in someapplications, as can larger droplets in others. A typical deliveryvelocity is 10 m/s, but other velocities may be appropriate inparticular applications. Because of the manner in which the dose isdelivered, this provides a significant benefit over traditionaltreatment techniques in which large doses of say 50 μl are used. Using adevice according to the invention in ocular treatment a much greaterproportion of treatment liquid will actually make effective contact withthe eye, leading to less wastage, reduced risk of systemic absorptionand less flooding of the eye and risk of provoking blinking or wateringwhich can result in a treatment being wasted.

[0081] Ophthalmic treatment fluids that may be used with the inventionmay be aqueous or non-aqueous liquids, optionally containing atherapeutic compound or compounds such as:

[0082] 1) Anti-glaucoma/IOP (intra-ocular pressure) lowering compounds

[0083] a) β-adrenoceptor antagonists, e.g. carteolol, cetamolol,betaxolol, levobunolol, metipranolol, timolol, etc.

[0084] b) Miotics, e.g. pilocarpine, carbachol, physostigmine, etc.

[0085] c) Sympathomimetics, e.g. adrenaline, dipivefrine, etc.

[0086] d) Carbonic anhydrase inhibitors, e.g. acetazolamide,dorzolamide, etc.

[0087] e) Prostaglandins, e.g. PGF-2 alpha.

[0088] 2) Anti-microbial compounds (including anti-bacterials andanti-fungals), e.g. chloramphenicol, chlortetracycline, ciprofloxacin,framycetin, fusidic acid, gentamicin, neomycin, norfloxacin, ofloxacin,polymyxin, propamidine, tetracycline, tobramycin, quinolines, etc.

[0089] 3) Anti-viral compounds, e.g. acyclovir, cidofovir, idoxuridine,interferons, etc.

[0090] 4) Aldose reductase inhibitors, e.g. tolrestat, etc.

[0091] 5) Anti-inflammatory and/or anti-allergy compounds, e.g.steroidal compounds such as betamethasone, clobetasone, dexamethasone,fluorometholone, hydrocortisone, prednisolone etc. and non-steroidalcompounds such as antazoline, bromfenac, diclofenac, indomethacin,lodoxamide, saprofen, sodium cromoglycate, etc.

[0092] 6) Artificial tear/dry eye therapies, comfort drops, irrigationfluids, etc., e.g. physiological saline, water, or oils; all optionallycontaining polymeric compounds such as acetylcysteine,hydroxyethylcellulose, hydroxymellose, hyaluronic acid, polyvinylalcohol, polyacrylic acid derivatives, etc.

[0093] 7) Diagnostics, e.g. fluorescein, rose bengal, etc.

[0094] 8) Local anaethetics, e.g. amethocaine, lignocaine, oxbuprocaine,proxymetacaine., etc.

[0095] 9) Compounds which assist healing of corneal surface defects,e.g. cyclosporine, diclofenac, urogastrone and growth factors such asepidermal growth factor, etc.

[0096] 10) Mydriatics and cycloplegics e.g. atropine, cyclopentolate,homatropine, hysocine, tropicamide, etc.

[0097] 11) Compounds for the treatment of pterygium, such as mitomycinC, collagenase inhibitors (e.g. batimastat) etc.

[0098] 12) Compounds for the treatment of macular degeneration and/ordiabetic retinopathy and/or cataract prevention.

[0099] 13) Compounds for systemic effects following absorption into thebloodstream after ocular administration, e.g. insulin. The abovecompounds may be in the form of free acids or bases or alternately assalts of these. Combinations of compounds e.g. an anti-bacterialcombined with an anti-flammatory may be desirable for the optimizationof therapy in some instances. The compounds may be formulated as aqueousor non-aqueous (e.g. oil) solutions or suspensions. Formulations mayoptionally contain other formulation excipients, for example, thickeningagents such as gels, mucoadhesives and polymers, stabilisers,anti-oxidants, preservatives, pH/tonicity adjusters etc.

[0100] It will be appreciated that devices of the invention mightcomprise a single unit, as well as the modular systems illustrated inwhich the delivery mechanism and the treatment liquid source areprovided separately, or at least independent of each other. Modularsystems do of course enable a fluid or treatment liquid to be selected,and coupled to a delivery mechanism as desired. This enables the samedelivery mechanism to be used for different treatments. Such a device ofthe invention for institutional use can provide for such selection to beat least partially automated.

1. A method of creating a directed jet and/or stream of droplets forminga unit dose of treatment liquid comprising discharging such liquid froma sealed enclosure through an opening in a wall section thereof, theopening having a diameter in the range 20 to 200 μm, by pressurising theenclosure at a rate sufficent to generate a jet and/or stream ofdroplets with a minimum diameter of 20 μm and sufficient momentum tosustain substantially linear movement over a predetermined distance. 2.A method according to claim 1 wherein the enclosure is pressurised bycollapse of the wall thereof.
 3. A method according to claim 2 whereinthe wall includes a reinforced region to orient its collapse.
 4. Amethod according to any preceding claim wherein the enclosure ispressurised by the relative movement of at least one wail thereof.
 5. Amethod according to any preceding claim wherein the enclosure is ablister pack.
 6. A method according to any preceding claim wherein theliquid is discharged through the opening in a flat section of theenclosure wall.
 7. A method according to claim 5 and claim 6 wherein thewall section is at a planar base of the blister.
 8. A method accordingto any preceding claim including the step of removing a cover overlayingsaid wall section and the opening therein.
 9. A method according to anyof claims 1 to 7 wherein the opening is closed by a membrane, whichmembrane ruptures upon pressurisation of the enclosure.
 10. A methodaccording to any preceding claim wherein the treatment liquid is anophthalmic treatment fluid.
 11. A method according to any precedingclaim wherein the sealed enclosure is one of a plurality thereofconnected by a common supporting substrate, and including the step oflocating one of the containers at a dosing station prior to dischargingtreatment liquid therefrom.
 12. A method according to claim 8 and claim11 wherein the step of locating a container at a dosing station issynchronised with the removal of the cover.
 13. A method according toany preceding claim wherein the enclosure is pressurised by compressingthe enclosure from the outside and against the wall section thereof. 14.A method according to claim 13 wherein the enclosure is pressurised by apiston or hammer mechanism for urging towards the wall section of theenclosure an opposite section of the wall.
 15. A method according toclaim 13 wherein the enclosure is pressurised by a piezoelectricelement.
 16. A method according to claim 15 wherein the piezoelectricelement is a ring transducer disposed around the enclosure.
 17. A methodof treatment comprising a method according to any preceding claimwherein the generated jet and/or stream of droplets is directed at atreatment site.